The overall goal of this program project grant (PPG) continues to be the exploration of the cellular and molecular mechanisms of allogeneic bone marrow transplantation (BMT) and to serve as a translational research platform for novel therapeutic strategies for patients with hematologic malignancies. Graft versus host disease (GVHD) remains a major cause of morbility and mortality after allogeneic BMT and prevents this curative therapy from wider application in cancer patients;thus a long term goal for the entire area of BMT is to develop new strategies to separate a beneficial graft versus leukemia (GVL) effect from GVHD. This PPG contributes to that goal by: 1) exploring the cellular and molecular mechanisms of GVHD from several perspectives;and 2) functioning as a translational research platform for the application of these mechanistic insights in Phase l/ll clinical trials in BMT patients. The significance of these studies therefore lies in their potential to lead to novel therapies for cancer patients, particularly those with hematologic malignancies. The major theme of this PPG is the modulation of donor immune responses to allogeneic host tissues without removal of T cells from the donor graft. This theme of modulating the interactions among the cellular subpopulations that initiate and mediate GVHD develops in several ways and unifies the entire PPG increasing collaborations and interactions among project leaders and provides multiple opportunities for synergy. In this next cycle, the PPG components continue as three projects and three cores: Project 1 HDAC Inhibition to Prevent GVHD Project 2 A Novel Bioenergetic Strategy to Treat GVHD Project 3 GVHD Clinical Trials and Biomarkers Core A Administration and Biostatistics Core B Experimental BMT Core C Clinical Sample Database and Proteomics